The adhesion of circulating cancer cells to capillary endothelium is a critical step in the genesis of metastasis (1,2). Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin superfamily, mediates the adhesion of hematopoietic cells and activated leukocytes to proinflammatory cytokine-activated endothelial cells (3-5). However, the adhesive function of VCAM-1 may be usurped by animal and human cancer cells to potentiate experimental metastatic spread (6).
For example, IL-1β and TNF-α are known to potentiate the metastasis of VLA-4-expressing melanoma cells in lung tissue by a mechanism that involves the up-regulation of VCAM-1 expression by endothelial cells (7-9). It has also been demonstrated that IL-1 and TNF-α significantly contribute to hepatic colonization of B16M cells both in normal and lipopolysaccharide-treated mice (7,8,10-20). In addition, mannose receptor-mediated hepatic sinusoidal endothelium (HSE) cell activation involves autocrine IL-1β-mediated HSE cell expression of VCAM-1, leading to increased B16M cell adhesion and metastasis (21). It was also shown that IL-1β-activated HSE cells release VLA-4-stimulating factors, which potentiate B16M cell adhesion to HSE cells (11). Thus, IL-1β induces VCAM-1 expression and VLA-4-stimulating factor release from HSE cells, which may confer upon them an ability to create a prometastatic microenvironment for certain intrasinusoidally-arrested VLA-4-expressing cancer cells.
However, blocking IL-1β and TNF-α led to only a partial metastasis abrogation, indicating that other factors either compensating for their absence, or acting via alternative pathways are also involved. Furthermore, most of metastasizing cancer cells and the target tissues are unable to produce these pro-inflammatory cytokines. Moreover, endotoxin or mannose receptor ligand concentration usually does not sufficiently increase to induce proinflammatory cytokine release. Hence, the multiple mediators that evoke VCAM-1 upregulation and its involvement during capillary transit of cancer cells are not well characterized.
IL-18 (IFNγ-inducing factor) is a novel cytokine that shares structural features with the IL-1 family of proteins (22) and functional properties with IL-12 (23). It has been reported that IL-18 production from Kupffer cells activates both TNF-α and FAS ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury (24). More recently, it has been revealed that IL-18 also possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNF-α from CD3+/CD4+ and natural killer cells with subsequent production of IL-1β and IL-8 from the CD14+ population, thereby revealing an unexpected pivotal position of IL-18 in the cytokine hierarchy (25). However, its possible role in cancer metastasis has not yet been elucidated.
An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-γ (IFN-γ), IL-8 and activation of NF-κB in vitro. Administration of IL-18BP to mice abrogated circulating IFN-γ following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP is constitutively expressed in the spleen, belongs to the immunoglobulin superfamily and has limited homology to the IL-1 type II receptor. Its gene was localized on human chromosome 11q13 and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Several Poxviruses encode putative proteins highly homologous to IL-18BP, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T-cell response (28 and WO 99/09063). As described more particularly in WO 99/09063, IL-18BP and muteins, fused proteins, functional derivatives, active fractions or circularly permutated derivatives and mixtures thereof are capable of binding to IL-18 and/or capable of modulating the activity of IL-18 and/or capable of blocking the activity of IL-18.